Lung cancer is the leading cause of cancer-related mortality in China and the world, wherein non-small cell lung cancer (NSCLC), in particular NSCLC adenocarcinoma, accounts for approximately 85% of all cases (Jemal, A. et al., CA: a cancer journal for clinicians, 2009, 59:225-249). There are more than 90 kinds of tyrosine kinases which are related to NSCLC.
Receptor tyrosine kinases (RTKs) are mediators of extracellular signals through activation of downstream signaling pathways including ERK, AKT and/or STAT3 cascades to control cell growth, proliferation, survival and motility pathways. In particular, chromosome rearrangements, gene amplification, and point mutations in respective genes contribute to and/or result in abnormal and constitutive RTK activation which is in turn responsible for initiation and progression of many cancers, including NSCLC. The first targetable RTK identified in NSCLC was the anaplastic lymphoma kinase gene (ALK), wherein chromosomal rearrangements of ALK have been identified amongst which is as most common form the echinoderm microtubule-associated protein-like 4 (EML4)-ALK, i.e. comprising portions of the EML4 gene and the ALK gene, wherein several variants of EML4-ALK gene fusions have been identified. EML4-ALK gene fusions have been found in 3% to 7% of NSCLC (Takeuchi, K. et al., Nature medicine, 2012, 18:378-381, Kwak, E. L. et al., The New England journal of medicine, 2010, 363:1693-1703, Roskoski, R., Jr., Pharmacological research, 2013, 68:68-94). These percentages translate into significant numbers of patients due to the increasing number of NSCLC (Shaw, A. T. et al., Nature, 2013, 13:772-787). Furthermore, additional fusion partners besides EML4 have been identified and, besides, ALK activating point mutations and presence of additional gene copies have been observed in several further cancer types activating the signaling pathways downstream to ALK (Roskoski, R., Jr., Pharmacological research, 2013, 68:68-94). In the majority of cases, ALK chromosome rearrangements are non-overlapping with other gene abnormalities found in NSCLC, i.e. usually abnormalities in ALK and ROS1 gene each define a distinct patient subgroup (Alamgeer, M. et al., Current opinion in pharmacology, 2013, 13:394-401).
Chromosome rearrangement involving the oncogenic c-ros oncogenel (ROS1) RTK were later reported, wherein ROS1 gene has been found to be fused with several gene partners in NSCLC. Approximately 1% to 2% of NSCLC patients harbor multiple kinds of ROS1 chromosome rearrangement (Shaw, A. T. et al., Nature, 2013, 13:772-787). Chromosome rearrangements of either ROS1 or ALK which may be based on interchromosomal translocation or intrachromosomal deletion are accompanied by the fusion of a portion of the ROS1 or ALK protein that includes its entire tyrosine kinase domain with several partner proteins with resulting ROS1 fusion kinases or ALK fusion kinases being constitutively activated and driving cellular transformation (e.g. Lovly, C. M. and Pao, W., Science translational medicine, 2012, 4:1-5). Respective cancers become dependent on continued signaling triggered by said fusion kinases, also named “oncogene addiction” (Shaw, A. T. et al., Nature, 2013, 13:772-787). In particular, ROS1 or ALK fusion kinases activate growth and survival pathways necessary for the growth and survival of cancer cells, which pathways are reported to include auto-phosphorylation of either ROS1 or ALK and phosphorylation of AKT, ERK and STAT3.
Recent developments in targeted-based therapies have led to a major paradigm shift in oncology. Small-molecule tyrosine kinase inhibitors are provided to treat cancer patients who have tyrosine kinase gene fusions, such as ROS1 or ALK chromosome rearrangements. Several tyrosine kinase inhibitors proved to have promising effects in the clinical practice. For example, crizotinib, a potent ATP-competitive small molecule inhibitor of ALK, have now been approved by the FDA for treating NSCLC patients that harbor ALK rearrangements. Crizotinib shows marked anti-tumor activity both in vitro and in vivo as well as in clinical practice. Since the tyrosine kinase domains of ALK and ROS1 are very similar, with 77% identity within the ATP-binding sites, most ALK inhibitors have cross activity against ROS1. In one early clinical trial of crizotinib to treat NSCLC patients harboring ROS1 rearrangements, the objective response rate was 72%, the median duration of response was 17.6 months and median progression-free survival was 19.2 months. Although most patients with ROS1-positive NSCLC exhibit substantial clinical benefit from crizotinib, the efficacy of crizotinib is limited due to the development of drug resistances. Hence, ensuring durable response to crizotinib therapy represents a universal challenge as drug resistance proved to be common and based on several resistance mechanisms in patients treated with crizotinib. Accordingly, patients who responded to crizotinib will eventually experience disease progression despite continued treatment.
Thus, further potent RTK inhibitors for cancer therapy have to be identified. Accordingly, there is a strong need for new compounds which are able to target RTKs and sufficiently inhibit their kinase activity, in particular ROS1 or ALK kinase activity, which compounds can, thus, be used for cancer therapy, in particular for treatment of NSCLC.